Synthesis and biological assays of new H3-antagonists with imidazole and imidazoline polar groups

New histamine H3-receptor antagonists were synthesised and tested on rat brain membranes and on electrically stimulated guinea-pig ileum. The new compounds have a central polar group represented by a 2-alkylimidazole or a 2-thioimidazoline nucleus. The effect of the polar group basicity on the optimal length of the alkyl chain, connecting this group to a 4(5)-imidazolyl ring, was investigated. The best affinity values, obtained by displacement of [3H]-RAMHA from rat brain, were obtained for the 2-alkylimidazole derivatives (2a-f) with tetramethylene chain (pKi 8.03-8.97), having an intermediate basicity between that of the previously reported 2-thioimidazoles (1a-i) and that of 2-alkylthioimidazolines (3a-h). In contrast, a general lowering of affinity (pKi 5.90-7.63) was observed for compounds of the last series (3a-h), with a complex dependence on the terminal lipophilic group and chain length.     

Histological examination of gastric mucosal lesions induced by isolation in saline and cimetidine treated rat

It has been recently pointed out that the most reliable method of assessment of gastric mucosal injury is the microscopic examination of the tissue. The purpose of the present paper was, therefore, to study the histological features of gastric lesions induced by a six week isolation in rats. It has also been investigated whether a two week treatment, beginning four weeks after isolation, with cimetidine 80 and 160 mg kg-1 p.o. daily could protect the gastric mucosa. In saline treated rats, histological examination of haemorrhagic areas showed that both surface epithelium and gastric pits were damaged or even completely absent with a consequent surfacing of subepithelial vessels. Damage extended deeply into the gastric glands with evidence of necrotic cells in the corpus and fundus. Simultaneous occurrence of the process of restitution was evident. Cimetidine partially lessened the severity of damage and appeared to favour the restitution processes.     

Pharmacological activities of two new histamine analogs

The pharmacological properties of 2-aminohistamine and 2-amino-5-methylhistamine were studied and compared with those of histamine, 5-methylhistamine and dimaprit. The introduction of an amino group in position 2 of the histamine imidazole ring caused a reduction of histamine potency, mostly with respect to H1 receptors. Such disactivation was much more evident in its corresponding 5-methyl derivative. The pharmacological activity related to the chemical structure will be discussed in the paper.     

Influence of urea-equivalent groups in position 5 of 2-amino, 2-(1-aminoethylidenamino) and 2-guanidino thiazole derivatives on H2-receptor antagonist activity in gastric fistula cat

A series of thiazole derivatives, in which a side-chain with different urea-equivalent groups was introduced in position 5 of the heterocycle, have been tested as inhibitors of dimaprit-induced gastric acid and pepsin secretion in the gastric fistula cat. By comparing thein vivo and the previously reportedin vitro activity of these compounds, we can note a very close parallelism not only in the quality of their action but also in the estimates of pA₂ values. These data support an interdependence between the molecular substructures and the affinity for the H₂-receptor.     

Influence of urea-equivalent groups in position 5 of 2-amino, 2-(1-aminoethylidenamino) and 2-guanidino thiazole derivatives on H2-receptor antagonist activity in gastric fistula cat

A series of thiazole derivatives, in which a side-chain with different urea-equivalent groups was introduced in position 5 of the heterocycle, have been tested as inhibitors of dimaprit-induced gastric acid and pepsin secretion in the gastric fistula cat. By comparing the in vivo and the previously reported in vitro activity of these compounds, we can note a very close parallelism not only in the quality of their action but also in the estimates of pA2 values. These data support an interdependence between the molecular substructures and the affinity for the H2-receptor.     

Synthesis and biological activity of substituted 2-(4-imidazolyl)ethylamines

The synthesis of 2-(4-imidazolyl)ethylamines with hydrocarbon substituents on the heterocyclic ring or on the side-chain, from 2-acylbutyrrolactones (V) or from similar ester-type open structures (VII) is described in this paper. In particular, the results already obtained, show that the scheme given for the preparation of 2-(5-methyl-4-imidazolyl)ethylamines can be rendered general, by suitable variations correlated more with side-chain branching, than with the nature of the heterocyclic ring substituents. Synthetized imidazolyethylamines have been preliminarily tested for their properties towards H2 receptors and, secondly, towards H1 receptors.     

Evidence for two opposite effects of clonidine on gastric acid secretion in the dog

Summary The effects of clonidine on gastric acid secretion were studied in conscious dogs wih both gastric fistulae and Heidenhain pouches. Clonidine infused systemically at graded doses under basal conditions produced a significant increase in acid secretion from both gastric fistulae and Heidenhain pouches. Acid secretion from gastric fistulae submaximally stimulated by pentagastrin was dose-dependently reduced by clonidine while 2-deoxy-d-glucose-induced secretion was completely suppressed. Under these conditions a significant enhancement of secretion from Heidenhain pouches was recorded. An increase in acid secretion from both main stomachs and Heidenhain pouches was observed for clonidine with submaximal doses of bethanechol and histamine as stimulants, though clonidine showed no effect on maximal stimulation by histamine. The stimulant effect of clonidine from gastric fistulae and Heidenhain pouches under basal conditions was fully prevented by cimetidine, while the inhibitory effect of clonidine on acid secretion stimulated by pentagastrin from gastric fistulae was reversed by yohimbine.The present results suggest that clonidine displays two simultaneous yet opposite effects on dog gastric secretion. The inhibitory effect might be mediated through a decrease of vagally released acetylcholine following the activation of alpha₂-adrenoceptors both at central and peripheral sites, while the stimulatory effect probably depends on the histamine-like properties of the drug.Preliminary results were presented at the 8th International Congress of Pharmacology, Tokyo, July, 19–24, 1981